PD-1+ Tcf1+ CD8+ T cells from established chronic infection can form memory while retaining a stable imprint of persistent antigen exposure

Virus-specific PD1(+) Tcf1(+) memory-like CD8(+) T cells (TMLs) maintain the CD8(+) T cell response during chronic viral infection. However, the fate of these cells following cessation of persistent antigen exposure has been unclear. Here, we find that TMLs persist upon transfer into antigen-free hosts and form memory following recall stimulation. Phenotypic, functional, and transcriptome analyses show that TML-derived memory cells resemble those arising in response to acute, resolved infection, but they retain features of chronically stimulated cells, including elevated PD-1 and Tox and reduced cytokine expression. This chronic infection imprint is largely accounted for by constitutive Tox expression. Virus-specific Tcf1(+) CD8(+) T cells that persist after clearance of systemic infection also display a chronic infection imprint. Notwithstanding, renewed virus exposure induces a recall response, which controls virus infection in part. Thus, cessation of chronic antigen exposure yields a memory CD8(+) T cell compartment that reflects prior stimulation.